1. Field of the Invention
The novel semi-synthetic penicillins of the present invention are useful as antibacterial agents for the treatment of bacterial infections caused by gram-positive and gram-negative bacteria including especially Pseudomonas strains.
2. Description of the Prior Art
It is well-known that penicillin antibiotics generally inhibit the growth of various gram-positive and gram-negative bacteria and are effective in the treatment of infections caused by these organisms. It is also known that few penicillins exert any appreciable antimicrobial activity against Pseudomonas. For the last two decades, however, the incidence of Pseudomonas aeruginosa infection has progressively increased. Recently, some penicillin antibiotics have been synthesized which are reported to be useful as antipseudomonal antibiotics (e.g. carbenicillin, U.S. Pat. No. 3,142,673; sulbenicillin, U.S. Pat. No. 3,660,379; and ticarcillin, U.S. Pat. No. 3,282,926), but these penicillins exhibit only a relatively low potency against Pseudomonas aeruginosa necessitating the use of large amounts of them for effective treatment. Therefore, there remains a need for the synthesis of new penicillins which possess a high degree of anti-Pseudomonas activity.
Various N-acyl derivatives of ampicillin (or a derivative thereof in which the phenyl ring is replaced by substituted phenyl, thienyl or another aryl or heterocyclic radical) have been disclosed in the patent and scientific literature. Illustrative patents and patent publications disclosing such derivatives containing an .alpha.-heterocycliccarboxamido group (where the heterocyclic ring may be bicyclic or polycyclic) are given below. Those publications which are limited to monocyclic heterocyclic groups are deemed less relevant and therefore are not included here.
(a) U.S. Pat. No. 3,945,995 disclosing penicillins of the formula ##STR2## where R is an unsubstituted phenyl group or a substituted phenyl group having one or more hydroxyl groups or a cyclohexadienyl group and A represents a monocyclic or polycyclic nitrogen-containing heterocyclic aromatic ring. The 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety is not listed in the disclosure as being included within the definition of substituent "A", nor are any penicillins having such an "A" group illustrated or exemplified therein. (See also U.S. Pat. No. 4,005,075 having a substantially identical disclosure.)
(b) U.S. Pat. No. 3,953,428 disclosing ampicillin derivatives of the formula ##STR3## where R is selected from various nitrogen, sulfur or oxygen-containing mono-, bi- or polycyclic heterocyclic rings. The 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety is not included within the definition of substituent "R."
(c) U.S. Pat. No. 3,873,523 disclosing penicillins of the formula ##STR4## where R.sup.1 is one of several named alicyclic, aryl or heterocyclic radicals, R.sup.2 is hydrogen or, taken together with R.sup.1 represents the group ##STR5## and R.sup.3 is hydrogen or methyl. [See also U.S. Pat. No. 3,948,903, of which this is a divisional, having a similar disclosure.]
(d) U.S. Pat. No. 3,951,955 disclosing penicillins of the formula ##STR6## where A is a substituted or unsubstituted condensed aromatic carbocyclic or heterocyclic ring, R is hydrogen or lower alkyl, X is oxygen or sulfur, Y is hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl and Z is phenyl or thienyl. (See also U.S. Pat. No. 3,864,329, of which 3,951,955 is a divisional, having a similar disclosure. Neither of these patents include the 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl substituent within their scope.
(e) U.S. Pat. No. 3,954,733 disclosing penicillins of the formula ##STR7## where A is a benzene ring or a 5 or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms, Z is a nitrogen atom or a methylene group, X is an oxygen or sulfur atom, Y is hydrogen, lower alkoxycarbonyl or lower alkanoyl, R.sub.1 is hydroxyl or protected hydroxyl and R.sub.2 and R.sub.3 are hydrogen or halogen. The 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl substituent is not included within its scope.
(f) U.K. Pat. No. 1,440,216 disclosing compounds of the formula ##STR8## where R.sub.1 is hydrogen and R.sub.2 is optionally substituted phenyl, thienyl or furyl, n and m independently are 0 or 1 and B represents one of several named pyrimidyl radicals which do not include the 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety.
(g) U.S. Pat. No. 3,320,240 disclosing compounds of the formula ##STR9## where R is an optionally substituted alkyl, aralkyl, aryl or heterocyclic group and X is a direct linkage or a divalent aliphatic, aromatic or heterocyclic radical which may be substituted. The 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety is not listed, illustrated or exemplified as a possible "X" substituent.
(h) U.S. Pat. No. 3,939,150 disclosing penicillins of the formula ##STR10## where B is a p-hydroxyphenyl or cyclohexadienyl, A is a 5- or 6-membered single or fused ring which may contain one or more nitrogen atoms, an oxygen atom or a sulfur atom and R.sup.1, R.sup.2 and R.sup.3 each represent hydrogen, hydroxy, lower alkyl, nitro, halogen or an oxo group. No 4-oxo-4H-pyrimido-[1,2-b]pyridazin-3-yl "A" moieties are disclosed in this patent.
(i) French Patent Publication 2,191,556 (Farmdoc 23502U) disclosing penicillins of the formula ##STR11## where R' is lower alkyl and R.degree. is phenyl or chloro-substituted phenyl.
(j) U.S. Pat. No. 3,433,784 disclosing penicillins of the formula ##STR12## where R is phenyl or thienyl, R' is optionally substituted heterocyclic and n is 0 or 1. No compounds are disclosed where n=0 and R' is a 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety.
(k) West German Published Application 2,312,976 (Farmdoc 59216U) disclosing penicillins of the formula ##STR13## where ##STR14## is a heteroaromatic ring with 6 ring atoms of which 1 or 2 are nitrogen atoms, Y is hydrogen, (lower)-alkanoyl or (lower)alkoxy-carbonyl, and R.sub.1 and R.sub.2 inter alia may be taken together to form a (lower)alkylene chain, optionally substituted with an oxo group.
(1) U.S. Pat. No. 3,933,795 disclosing inter alia penicillins of the formula ##STR15## in which B is substituted or unsubstituted phenyl, thienyl, cyclohexen-1-yl or cyclohexa-1,4-dienyl, and "A" may be inter alia ##STR16## in which Q may be inter alia ##STR17## thus allowing "A" to be inter alia ##STR18## The extremely broad disclosure of "A" does not include the 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety, [See also U.S. Pat. Nos. 3,936,442, 3,939,149, 3,959,258, 3,972,869, 3,972,870, 3,974,140, 3,974,141, 3,974,142, 3,975,375, 3,978,056, 3,978,223, 3,980,792 and 3,983,105 having substantially the same disclosure.]
(m) U.S. Pat. No. 3,992,371 disclosing penicillins of the formula ##STR19## in which R.sup.1, R.sup.2 and R.sup.3 are hydrogen or any of various named substituents, ##STR20## represents inter alia a substituted or unsubstituted nitrogen-containing heteroaromatic ring, ##STR21## represents a pyridine, pyrazine or pyridazine ring, X is oxygen or sulfur, and Y is hydrogen, (lower)alkoxycarbonyl or (lower)alkanoyl. Although this disclosure encompasses numerous bicyclic heterocyclic groups, the 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl moiety is not included therein. This is most easily seen by the fact that this patent discloses only bicyclic heterocyclic compounds in which both bridgehead atoms are carbon. In the novel compounds of the instant invention, one of the bridgehead atoms of the bicyclic heterocyclic group is nitrogen.
(n) Belgian Patent 836,022 (Farmdoc 46019X) disclosing inter alia penicillins of the formula ##STR22## in which B may be substituted or unsubstituted phenyl, cyclohexenyl or cyclohexadienyl, A may be inter alia 1,2-phenylene, and Z is ##STR23## in which R.sup.1 and R.sup.2 may be hydrogen, alkyl cycloalkyl, aralkyl, aryl, heterocyclyl, COOH, CN, NO.sub.2, CONH.sub.2, etc., or R.sup.1 and R.sup.2 taken together may complete a 3-7 membered carbocyclic or heterocyclic ring. Thus, the closest teaching of this patent is to penicillins of the formula ##STR24## wherein B and Z are as defined above.
(o) U.S. Pat. No. 4,081,545 discloses penicillins of the formula ##STR25## wherein R represents a furyl, thienyl, cycloalkyl, cycloalkenyl or phenyl group, or a phenyl group substituted by hydroxy, halogen, nitro, lower alkyl, lower alkoxy, amino or carboxy; and A and B are the same or different and each represents the residue of a substituted or unsubstituted fused 5- or 6-membered ring; and pharmaceutically acceptable non-toxic salts and in vivo hydrolyzable esters thereof. The patent names or shows the structure for numerous [4,4,0] heterocyclic ring systems containing from 1 to 3 nitrogens, [4,3,0] heterocyclic ring systems containing from 1 to 5 nitrogens, and [4,3,0] heterocyclic ring systems containing up to three nitrogens plus oxygen or sulfur. Although the 4-oxo-4H-pyrimido[1,2-b]pyridazin-3-yl ring system is one of the numerous heterocyclic ring systems depicted, there is no disclosure whatever as to a method of preparing the 7-hydroxy-4-oxo-4H-pyrimido[1,2-b]pyridazin-3-ylcarboxylic acid or the corresponding acid halide. Further, the patent teaches that ring A preferably is 5-membered.
(p) Tetrahedron Letters, (1), 33-36 (1968) discloses the preparation of 3-carbethoxypyrimido[1,2-b]-pyridazin-4-one, but there is no disclosure of a means of preparing the 7-hydroxy-4-oxo-4H-pyrimido[1,2-b]pyridazin-3-ylcarboxylic acid or the corresponding acid halide.
(q) J. Organic Chemistry, 36, 2457-2462 (1971) discloses the preparation of 3-carbethoxypyrimido[1,2-b]-pyridazin-4-one and 3-carbethoxy-7-chloropyrimido[1,2-b]-pyridazin-4-one, but there is no disclosure of a means of preparing the 7-hydroxy-4-oxo-4H-pyrimido[1,2-b]pyridazin-3-ylcarboxylic acid or the corresponding acid halide.